Opiate intermediates and methods of synthesis

ABSTRACT

Novel opiate intermediate compositions and methods of synthesis that include changing the substitution pattern on the aromatic ring of the pre-Grewe intermediate are provided. The intermediates are morphinane derivatives of formula (10), wherein X is a F or Cl and R is selected from the group consisting of an H, alkyl, aryl, acyl, formyl, COR″, CONHR″, COOR, Bn(benzyl), alkyl(methyl), and sulfonamide SO 2 CH 2 COPh.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage application of PCT/US2005/038140,filed Oct. 21, 2005, which claims the benefit of U.S. ProvisionalApplication No. 60/625,397 filed Nov. 4, 2004, both of which areincorporated herein in their entirety.

BACKGROUND OF INVENTION

The morphinan alkaloids represent a family of structurally relatednatural products of great medicinal importance. An efficient totalsyntheses of the (−)-morphine and select derivatives has therefore beenthe objective of many synthetic efforts in the past century. Although anumber of routes have been completed, all require long syntheticcampaigns through numerous steps resulting in low overall yields and insome cases providing only racemic material. None are suitable forscale-up to a standard manufacturing process. Therefore, a practicalmethod is needed that minimizes the number of steps and intermediateisolations, that is robust; that requires economical reagents andstarting materials and that maximizes overall yield. To realize thesegoals, the methods disclosed in U.S. Pat. Nos. 4,368,326, 4,521,6015,668,285 to Rice et al. (hereinafter Rice) and H. C. Beyerman, E.Buurman, L. Maat and C. Olieman, Recl. Trav. Chim. Pays-Bas 95, 184(1976) (hereinafter Beyerman) have been used as basis for a hybridsynthesis into the morphinan ring system primarily focused on improvingthe key Grewe cyclization step.

Grewe cyclization is a ring closure method that in the present inventionutilizes bromine or other halogens as a positional blocking group. Thedeactivating influence of halogen on the phenolic ring is overcome bythe use of “super” acids in the Grewe cyclization (J. Het. Chem. June1974, 363).

In the Beyerman synthesis, the key intermediate has an additionalhydroxyl substitution on the aromatic ring that allows for Grewecyclization under milder acid conditions, HCl/ethyl ether, but requiresa subsequent dehydroxlation step to remove this activating function.

The Rice intermediates that undergo Grewe cyclization contain a methoxy,o-hydroxyl and m-bromo substitution pattern on the aromatic ring. Sincethese functions do not electron donate as much as three hydroxyls(Beyerman), a “super” acid medium, triflic acid, must be used to formthe morphinan ring system. Any water contamination in the trifle acidgreatly reduces the yield by the formation of a α,β-bicyclic-ketone andits polymerization by-products. Therefore, the Rice synthesis has acritical cyclization reaction in the middle of the route with verylimited, severe, expensive acid requirements.

The dissolving metal reduction reaction well known in the art as theBirch reduction is used for reducing compounds, including the reductionof aromatic compounds to 1,3-cyclohexadiene or 1,4-cyclohexadiene anddehalogenation reactions. Although run under severe reaction conditions,the reduction is an important transformational tool for chemists and hasbeen widely applied in organic synthesis in the partial reduction of anaromatic ring to 1,4-cyclohexadienes or 1,3-cyclohexadienes. Reductionof other functional groups on an aromatic ring or olefin, including theC—X bond, wherein X is a halogen, to C—H usually occurs.

The dissolving metal reduction comprises reacting with an alkali metalin the presence of a nitrogen containing base, usually ammonia. Thealkali metal is typically Li, Na, K or Ca in a solvent system includingsimple alcohols and ethers held at reduced temperature.

The modified reduction reaction utilized in the present inventionprovides a method for preventing the reduction of at least one halogensubstituted aromatic ring of an aromatic compound, while allowing thereduction of at least one functional group on the aromatic compound.This method is the subject of co-pending provisional application Ser.No. 60/534,592, filed Jan. 6, 2004, to the same assignee as the presentinvention. In this presently preferred method, at least one hydroxylgroup and one halogen are substituted on the aromatic ring that does notundergo reduction. The aromatic compound is then reacted with at leastone alkali metal in at least one nitrogen containing base and at leastone alcohol, while maintaining a ratio of the alcohol to the nitrogencontaining base. At least, one halogen substituted aromatic ring with ahydroxyl function is protected from reduction, while the desired groupis reduced.

The reaction requires mild reaction conditions for the dissolving metalreduction. The modified metal reduction uses an alkali metal, typicallylithium, sodium, potassium, calcium or a mixture thereof as a reductivereagent. The reaction further includes a nitrogen containing base,typically ammonia or a lower amine, and the presence of at least onealcohol. Suitable lower amines include but are not limited to ammonia,methylamine, ethylamine, ethylenediamine and mixtures thereof. Thefollowing solvent/nitrogen bases are particularly well suited for thepresent invention: a mixture of at least one alcohol and ammonia or atleast one lower amine, or at least one alcohol, ammonia or at least onelower amine and at least one organic co-solvent. Suitable organicco-solvents include but are not limited to THF, ether and mixturesthereof. The dissolving metal reduction is carried out at a reducedtemperature and at a ratio of nitrogen containing base to alcohol atwhich the reduction or dehalogenation of the protected aromatic ring isprevented. A presently preferred ratio of alcohol to nitrogen containingbase is about 1:1 to about 1:4. The reaction temperature is typicallymaintained at about −30° C. or lower.

SUMMARY OF INVENTION

In one aspect of the present invention a method for the synthesis of anopiate intermediate is provided. The method comprises:

a) reacting a compound of Formula 1

-   -   wherein X is F or Cl;

with at least one halide selected from the group consisting of sulfonylhalide and phosphorous halide to form a compound of Formula 2;

-   -   wherein X is a F or Cl; —X₁ is a Cl or Br; and wherein Y is SO        when the halide is sulfonyl halide, and PCl when the halide is        phosphorous halide;

b) reacting the compound of Formula 2 with a compound of Formula 3

-   -   wherein R′ is an alkyl, aryl or acyl group, in the presence of a        base to form a compound of Formula 4;

-   -   wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group,

c) reacting the compound of Formula 4 with at least one phosphorylhalide and then hydrolyzing to form a compound of Formula 5;

-   -   wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group,

d) reacting the compound of Formula 5 as a free imine or imine salt witha reducing agent to form a compound of Formula 6;

-   -   wherein X is a F or Cl and R′ is an alkyl, aryl or acyl group,

e) selectively reducing the compound of Formula 6 to form a compound ofFormula 7;

-   -   wherein X is a F or Cl and R′ is an alkyl, aryl or acyl group,

f) reacting the compound of Formula 7 with at least one formic acidester, acyl halide, alkyl or aryl anhydride, alkyl haloformate, benzylhalide, alkyl halide or phenacylsulfonyl halide to form a compound ofFormula 8;

-   -   wherein X is a F or Cl; R′ is an alkyl, aryl, or acyl and R is        selected from the group consisting of formyl (CO), COR″, COOR″,        Bn(benzyl), alkyl(methyl, ethyl, n-propyl, isopropyl, n-butyl,        isobutyl, cyclopropylmethyl, cyclobutylmethyl, allyl, and etc.),        and sulfonamide SO₂CH₂COPh, and wherein R″ is selected from the        group consisting of alkyl and aryl.

g) hydrolysis of the compound of Formula 8 forms a compound of Formula9; and

-   -   wherein X is a F or Cl; and R is an H, alkyl, aryl, acyl,        formyl, COR″, COOR″, Bn(benzyl), alkyl(methyl), and sulfonamide        SO₂CH₂COPh.

h) converting the compound of Formula 9 under Grewe cyclizationconditions in a strong acid to form the morphinan backbone, the compoundof Formula 10.

-   -   wherein X is a F or Cl and R is selected from the group        consisting of formyl, COR″, COOR″, Bn(benzyl), alkyl(methyl),        and sulfonamide SO₂CH₂COPh.

In another aspect of the present invention the following novel opiatesynthesis intermediates are provided:

wherein X is a F or Cl and R′ is an alkyl, aryl or acyl group;

wherein X is a F and Cl and R′ is an alkyl, aryl or acyl group;

wherein X is a F or Cl and R′ is an alkyl, aryl or acyl group;

wherein X is a F or Cl and R′ is an alkyl, aryl or acyl group;

wherein X is a F or Cl and R is an H, alkyl, aryl or acyl group; and

wherein X is a F or Cl and R is an H, alkyl, aryl or acyl group.

DETAILED DESCRIPTION

It has been determined that by changing the substitution pattern on thearomatic ring of the pre-Grewe intermediate from methoxy, o-hydroxyl andm-bromo (as disclosed by Rice) to dihydroxyl and m-halide(Cl or Br), theneed for a “super” acid is obviated. Although the reaction stillproceeds in triflic acid, much milder acids including but not limited tomethanesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoricacid, p-toluenesulfonic acid, benzenesulfonic acid and boron trifluorideetherate can be used with much more tolerance to the presence of water.Further, the reaction is more robust and rearrangement to theα,β-bicyclic-ketone is minimized. Moreover, polymerization is mitigated.This route is also superior to that disclosed by Beyerman, since nodihydroxylation step required.

Therefore, there are provided novel opiate intermediates and an improvedmethod for the synthesis of opiate intermediates. An embodiment of thepresent method comprises reacting a compound of Formula 1

wherein X is a F or Cl;

with a sulfonyl halide or a phosphorous halide to form a compound ofFormula 2. Suitable sulfonyl halides include SOCl₂ and SOBr₂ with SOCl₂being preferred. Suitable phosphorous halides include PBr₃, PCl₃ andPCl₅. The halide reacts with the diol to form the heterocyclic ring ofFormula 2. In an illustrative embodiment Formula 1 is heated to refluxin SOCl₂/toluene for about 3 hours, after which the solvent is removedby distillation.

wherein Y is SO; X is F or Cl and X₁ is Cl or Br. In an embodiment wherea phosphorous halide is utilized, Y would be PCl.

Formula 2 is then reacted with a compound of Formula 3 in the presenceof a base to form a compound according to formula 4. Suitable basesinclude alkali bicarbonates, alkali carbonates, alkali phosphates(di-and tri-), ammonium hydroxide, ammonium acetate, organic buffers such asBICINE, TRICINE, TRIS, CAPS, CAPSO, EPPS, HEPES, MES, MOPS, PIPES, TAPS,TES or their sodium salts; organic bases like pyridine, triethylamine,diisopropylethylamine, N-methylmorpholine, N,N-dimethylaminopyridine ormixtures thereof. In an illustrative embodiment formula 2 is added to amixture of NaHCO₃/Na₃CO₃/NaHSO₃/H2O and Formula 3. After stirring thelayers were separated to recover Formula 4 from the organic layer.

wherein R′ is an alkyl, aryl or acyl group

The compound of Formula 4 is then treated with at least one phosphorylhalide followed by hydrolysis to form a compound according to Formula 5.Suitable phosphoryl halides include POCl₃ and POBr₃, with POCl₃ beingpreferred. Suitable methods of hydrolysis include aqueous reflux atadjusted pH. Typical bases utilized to adjust the pH to a desired rangeinclude alkali carbonates, alkali phosphates, sodium hydroxide, sodiumacetate, ammonium acetate or ammonium hydroxide. In an illustrativeembodiment, the compound of Formula 4 heated to a temperature inPOCl₃/acetonitrile at which it completely dissolves is taken to reflux.An oily product is recovered, re-dissolved in acetonitrile, pH adjustedto 4-5 and refluxed. Formula 5 is produced as a crystalline solid.

Formula 5 as a free imine is then reduced to form Formula 6. Suitablereduction reactions include NaBH₄, NaCNBH₃, H₂ and Pt, Pd, Ir, Ru or Rhon Carbon in a solvent such as ethanol, methanol, isopropanol, propanol,formic, formate salt and acid, THF, ethyl acetate, and mixtures thereof.In an alternative embodiment of the present invention, chiralorganometallic catalysts (Ru, Rh, Ir, Pt, Pd, . . . bearing chiralligands) or chiral hydrides may be used to induce the enantiomericcenter at the benzylic position adjacent to the nitrogen. In the chiralcase, for example, sodium triacyloxyborohydride generated fromN-benzyloxycarbonylproline and borohydrides has been used to preparesimilar enantiomeric tetrahydroquinolines from the corresponding imines.(For illustrative examples consult pages 230-240 of “Chiral Auxiliariesand Ligands in Asymmetric Synthesis” by Jacqueline Seyden-Penne, JohnWiley & Sons publisher, NY, 1995) In an illustrative embodiment ofreduction to the racemate, the compound of Formula 5 is refluxed inethanol, after which NaBH₄ is added.

Formula 6 is then selectively reduced to form a compound of Formula 7.The reaction requires mild reaction conditions for the dissolving metalreduction. The modified metal reduction uses an alkali metal, typicallylithium, sodium, potassium, calcium or a mixture thereof as a reductivereagent. The reaction further includes a nitrogen containing base,typically ammonia or a lower amine, and the presence of at least onealcohol. Suitable lower amines include but are not limited to ammonia,methylamine, ethylamine and mixtures thereof. The followingsolvent/nitrogen bases are particularly well suited for the presentinvention: a mixture of at least one alcohol and ammonia or at least onelower amine, or at least one alcohol, ammonia or at least one loweramine and at least one organic co-solvent. Suitable organic co-solventsinclude but are not limited to THF, ether and mixtures thereof. Thedissolving metal reduction is carried out at a reduced temperature andat a ratio of nitrogen containing base to alcohol at which the reductionor dehalogenation of the protected aromatic ring is prevented. Apresently preferred ratio of alcohol to nitrogen containing base isabout 1:1 to about 1:4. The reaction temperature is typically maintainedat about −30° C. or lower.

In an illustrative embodiment formula 6 is suspended in ethanol/ammoniaand cooled to about −70 C under nitrogen. NaOEt is added, followed bycut sodium metal. Upon completion, the reaction mixture is allowed towarm, the reaction is quenched and a suspension of compound of Formula 7is recovered.

Formula 7 is reacted with at least one formic acid ester to form Formula8. Suitable formic acid esters include HCO₂Pr, HCO₂Et, HCO₂Bn, HCO₂Me,HCO₂nBu, HCO₂Ph and mixtures thereof. In an illustrative embodiment,Formula 8 is suspended in HCO₂Pr and heated to reflux. After the solventis removed, a powder residue comprised of the compound of Formula 8remains. Optionally, the compound of Formula 8 may be used in thesubsequent process step.

Formula 8 is hydrolyzed to form a compound of Formula 9. Suitablehydrolysis reactions include aqueous acetic acid, or other aqueous acidsat a controlled pH, as are well known in the art. In an illustrativeembodiment, Formula 8 is mixed with formic acid and the compound ofFormula 9 is then extracted with ethyl acetate.

Formula 9 is then converted to formula 10 under Grewe cyclizationconditions. The Grewe method is an acid catalyzed ring closure of asubstituted tetrahydroisoquinoline to the corresponding morphinan ringsystem, as is well known in the art. Suitable acid medium include butare not limited to methanesulfonic acid, p-toluenesulfonic acid,benzenesulfonic acid, sulfuric acid, trifluoroacetic acid,trifluoromethanesulfonic acid, phosphoric acid and mixtures thereof.Optionally, the acidic media may consist of a Lewis acid in solutionsuch as boron trifluoride etherate. In an illustrative embodimentformula 9 is dissolved in CHCl₃ and added to the acidic medium chosenfrom the group including but not limited to methanesulfonic acid,p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid,trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid andmixtures thereof

In an alternative embodiment

wherein X is a halogen and R is H, alkyl, acyl, aryl or R is selectedfrom the group consisting of formyl, COR″, COOR″, Bn(benzyl),alkyl(methyl), and sulfonamide SO₂CH₂COPh.

In yet another alternative embodiment

wherein X is a halogen and R is H, alkyl, acyl, aryl, formyl, COR″,COOR″, Bn(benzyl), alkyl(methyl), and sulfonamide SO₂CH₂COPh.

A non-limiting illustrative example of the reaction scheme of thepresent invention follows. The reactions are explained in detail in theexamples that follow.

The following novel compounds are illustrative of the types of compoundsthat can be synthesized by the instant method. These compounds are in noway all inclusive or limiting of the present invention.

Formula 204-chloro-5-((1,2,3,4,5,8-hexahydro-6-methoxyisoquinolin-1-yl)methyl)benzene-1,2-diol

4-chloro-5-(((R)-1,2,3,4,5,8-hexahydro-6-methoxyisoquinolin-1-yl)methyl)benzene-1,2-diol

4-chloro-5-(((S)-1,2,3,4,5,8-hexahydro-6-methoxyisoquinolin-1-yl)methyl)benzene-1,2-diol

Formula 27

1-(2-fluoro-4,5-dihydroxybenzyl)-3,4-dihydro-6-methoxyisoquinoline-2(1H,5H,8H)-carbaldehyde

(R)-1-(2-fluoro-4,5-dihydroxybenzyl)-3,4-dihydro-6-methoxyisoquinoline-2(1H,5H,8H)-carbaldehyde

(S)-1-(2-fluoro-4,5-dihydroxybenzyl)-3,4-dihydro-6-methoxyisoquinoline-2(1H,5H,8H)-carbaldehydeFormula 284-fluoro-5-((1,2,3,4,5,8-hexahydro-6-methoxyisoquinolin-1-yl)methyl)benzene-1,2-diol

4-fluoro-5-(((R)-1,2,3,4,5,8-hexahydro-6-methoxyisoquinolin-1-yl)methyl)benzene-1,2-diol

4-fluoro-5-(((S)-1,2,3,4,5,8-hexahydro-6-methoxyisoquinolin-1-yl)methyl)benzene-1,2-diolFormula 291-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,7,8-hexahydroisoquinolin-6(5H)-one

(R)-1-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,7,8-hexahydroisoquinolin-6(5H)-one

(S)-1-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,7,8-hexahydroisoquinolin-6(5H)-oneFormula 301-(2-chloro-4,5-dihydroxybenzyl)-3,4,6,7,8,8a-hexahydro-6-oxoisoquinoline-2(H)-carbaldehyde

(R)-1-(2-chloro-4,5-dihydroxybenzyl)-3,4,5,6,7,8-hexahydro-6-oxoisoquinoline-2(1H)-carbaldehyde

(S)-1-(2-chloro-4,5-dihydroxybenzyl)-3,4,5,6,7,8-hexahydro-6-oxoisoquinoline-2(1H)-carbaldehydeFormula 311-(2-chloro-4,5-dihydroxybenzyl)-1,4,4a,5,6,8a-hexylydro-6-oxoisoquinoline-2(3H)-carbaldehyde

(1R)-1-(2-chloro-4,5-dihydroxybenzyl)-1,4,4a,5,6,8a-hexahydro-6-oxoisoquinoline-2(3H)-carbaldehyde

(1S)-1-(2-chloro-4,5-dihydroxybenzyl)-1,4,4a,5,6,8a-hexahydro-6-oxoisoquinoline-2(3H)-carbaldehydeFormula 321-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,4a,5-hexahydroisoquinolin-6(8aH)-one

(1R)-1-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,4a,5-hexahydroisoquinolin-6(8aH)-one

(1S)-1-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,4a,5-hexahydroisoquinolin-6(8aH)-oneFormula 331-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,8,8a-hexahydroisoquinolin-6(7H)-one

(1R)-1-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,8,8a-hexahydroisoquinolin-6(7H)-one

(1S)-1-(2-chloro-4,5-dihydroxybenzyl)-1,2,3,4,8,8a-hexahydroisoquinolin-6(7H)-one

As with the scheme and compounds given above, the examples herein areprovided for purposes of illustration only and are not intended in anyway to be limiting of the present invention.

EXAMPLES Example 1 Chlorination of Formula 14

Formula 14 (238.0 g, 1.21 mol) when added to THF/c-HCl (1250 mL/125 mL)formed a yellow solution. The solution was cooled down to −10° C. in adry-ice/i—PrOH bath. N-chlorosuccimide (NCS) (170.0 g, 1.05 eq) wasadded in five portions over a 2 h period. Water (1200 mL) was thenadded. Solvent (˜1500 mL) was distilled off until distillate vaportemperature reached 100° C. The mixture with stirring was allowed tocool down overnight to give crystals. It was filtered. The filtrate(1250 mL) was obtained and HPLC analysis indicated that it contained 5grams of product. The solid was washed with water (200 mL, 150 mL×2) anddried in flowing air for 4 hours to give 326.8 g of wet solid of pureproduct by HPLC analysis.

Example 2 Preparation of Formula 15

The crude product of Example 1 was suspended in 48% HBr and heated to90° C. for form a brown solution. It was stirred at 90° C. for 6 h,heated at 100° C. for 3 h and then cooled to room temperature. Thesuspension was left stirring over the weekend. The mixture was filteredand the recovered solid was washed with water (600 mL). The solid wasdried in flowing air for 4 h to give 256 g of solid. It was dissolved inrefluxing ethyl acetate (1000 mL). 100 grams of activated carbon wasadded. The mixture was refluxed for another 10 minutes and filtered hot.The filter was washed with hot ethyl acetate (250 mL×2). The combinedorganic solutions were taken to dryness under vacuum, and the product(156.05 g) was recovered as off white solid.

Example 3 Preparation of Formula 15

To a solution of the dried product of Example 1 (55.0 g, 0.238 mol) inCH₂Cl₂ (500 mL) at 10° C., BBr₃ (50 mL, 2.2 eq) was added. The mixturewas stirred for 30 minutes after the addition was completed and thenpoured into water (1000 mL), it was heated to reflux for 1 hour.Dichloromethane was removed by distillation until the distillate vaportemperature reached 100° C. The remaining solution was allowed to cooldown and then extracted with ethyl acetate (300 mL, 150 mL×2). Thecombined organic layers were washed with water (300 mL×2) and taked todryness under vacuum to give 41.5 g of product as solid.

Example 4 Preparation of Formula 18

The compound of Example 3 (38.4 g, 0.19 mol) was heated to reflux inSOCl₂/toluene (120 mL/300 mL for 3 hours. 260 Milliliters of solventwere distilled off under reduced pressure at 60° C. The solution wascooled down to room temperature. It was added to a mixture ofNaHCO₃/NaHSO₃/H₂O (80 g/15 g/800 mL) and ethyl acetate (35 g of 17/400mL) over 20 minutes. The mixture was stirred for another 30 minutesafter the addition and then the layers were separated. The aqueous layerwas extracted with ethyl acetate (400 mL). The combined organic layerswere washed with NaHCO₃/NaHSO₃/H₂O (80 g/15 g/800 mL), 400 mL×2. Theorganic layers were washed in 1N HCl (500 mL, 250 mL×2). The solvent wasremoved under reduced pressure affording the product as a sticky oil,56.2 g.

Example 5 Preparation of Formula 19

The compound of Example 4 (56.2 g) was dissolved in POCl₃/ACN (50 mL/250mL) at 50° C. for 1 hour and then refluxed for 1 hour. The solution wastaken to dryness under vacuum. It was re-dissolved in ACN (350 mL) andpoured into water (500 mL). The mixture was heated to reflux and the pHwas adjusted to 3-4. The heating at reflux was continued for 18 hours.350 mL solvent was removed by distillation. The solution was cooled to80° C. ACN (50 mL) was added and further cooling of the solution to 10°C. provided crystals. The crystals were separated by filtration. Thesolid was washed with water (100 mL×2, 50 mL) and dried under an airflow overnight to give 44.2 g of solid.

Example 6 Chlorination of the Compound of Formula 14

The compound of Formula 14 (229.0 g, 1.17 mol) was added to THF/c-HCL(1000 mL/100 mL) forming a yellow solution. It was cooled to 5-10° C.over ice bath. N-Chlorosuccinimide (NCS, 164.0 g, 1.05 eq) was added infour portions over 1 hour. The mixture was stirred and maintained atabout 10° C.-20° C. during and for 30 minutes following the addition.The mixture was allowed to warm to RT with stirring over another 30minutes. Water (1000 mL) was added. THF was removed by distillationuntil the distillate vapor temperature reached 100° C. The remainingliquid was allowed to cool to 5° C. with stirring over 2 hours. Thecrystals formed on cooling were filtered. The solid was washed withwater (200 mL, 150 mL×2) and dried in flowing air for 18 hours to give266.3 g.

Example 7 Preparation of Formula 15

The crude product yield of Example 6 (265 g) was suspended in 48% HBr(1000 mL) and heated at 95° C. for 1 hour and then taken to reflux for 3hours. A crystalline solid formed on cooling to 5° C. The crystals wereseparated by filtration. The crystals were washed with water (200 mL,150 mL) and dried under house vacuum at 70° C. for 3 hours to give 158.5g of product.

Example 8 Preparation of Formula 18

The compound of Example 7 (10.1 g, 50.0 mmol) was heated to reflux inSOCl₂/toluene (10.9 mL/100 mL) for 3 hours. The solvent (50 mL) mainlySOCl₂ was removed by distillation. The reaction mixture was cooled to25° C. and added to a mixture of NaHCO₃/Na₃CO₃/NaHSO₃/H₂O (16.8 g/10.6g/2.6 g/200 mL) and ethyl acetate (9.1 g 17/100 mL) over 20 minutes. Themixture was set aside with stirring for 30 minutes after the addition.The phases were separated, and the aqueous layer was extracted withethyl acetate (50 mL×2). The combined organic layers were washed with100 mL of NaHCO₃/NaHSO₃/H₂O (15 g/3 g/150 mL) and then 50 mL×3. Theorganic layer was washed with 1 N HCl (100 mL, 50 mL×2). The solvent wasremoved under reduced pressure to give sticky solid, 15.2 g.

Example 9 Preparation of formula 18

The compound of Example 7 (101.3 g, 0.5 mmol) was heated to reflux inSOCl₂/toluene (109 mL/1000 mL) for 3 hours. Solvent (500 mL) was removedby distillation. The remaining solution was cooled to 25° C. and addedto a mixture of NaHCO₃/Na₃CO₃/NaHSO₃/H₂O (168 g/106 g/26 g/1500 mL) andethyl acetate (91 g of 17/800 mL) over 20 minutes. The mixture was setaside with stirring for 30 minutes after the addition. The phases wereseparated, and the aqueous layer was extracted with ethyl acetate (700mL). The combined organic layers were washed with NaHCO₃/NaHSO₃/H₂O (50g/3 g/700 mL) and then 400 mL×2. The organic layer was washed with 1 NHCl (700 mL, 400 mL×2). The solvent was removed under reduced pressureto give a sticky solid, 150.4 g.

Example 10 Preparation of Formula 19

The compound of Example 9 (150 g) was dissolved in POCl₃/ACN (163 mL/750mL) at 50 C for 1 hour and then refluxed for 1 hour. An oily materialwas recovered after the volatiles were removed under reduced pressure.The oil was re-dissolved in ACN (750 mL) and poured into water (1500mL). The mixture was heated to reflux and the pH was adjusted to 4-5.Heating at reflux was continued for 22 hours. Once the solvent (850 mL)had been removed by distillation, the solution was cooled down to 80° C.After the ACN (150 mL) was added, the solution was allowed to cool to10° C. to give crystals. The crystals were separated by filtration. Thesolid was washed with water (500 mL×2) and was dired under a flow of airovernight to give 131.5 g product as a solid.

Example 11 Preparation of Formula 20

The compound formed in Example 10 (100.0 g) was refluxed in EtOH (1000mL). NaBH₄ (21.1 g) was added in portions. Hydrogen was released duringthe addition but stopped 10 minutes post addition. The suspension washeated to reflux for 30 minutes. Water (1500 mL) was added slowly andconc. HCl (˜75 mL) was added until pH is 0-1. Solvent (1500 mL) wasremoved by distillation until the distillate temperature reached 99° C.After a solid began to form the mixture was allowed to cool to RT. After3 hours the solids were separated by filtration. The solid was washedwith water (100 mL×3) and dried under a flow of air for 1 hour to give173 g wet solid H₃PO₄ salt product.

The wet product (172 g) was dissolved in HCl (1N, 500 mL)/EtOH (500 mL)under reflux. The hot solution was added into a mixture of NH₄OH (29.4%,80 mL)/H₂O (400 mL)/ice (1000 g) with stirring to give a precipitate.The mixture was stirred for an additional hour. The solids wereseparated by filtration. The material was washed with water (200 mL, 200mL×3) and dried under a flow of air overnight to give 82.1 g.

Example 12 Preparation of Formula 21

The compound of Example 11 (28 g) was suspended in EtOH (750 mL) andcooled to −70° C. Ammonia (NH₃) was condensed into the EtOH to a finalvolume of 1500 mL at −70° C. The solution was kept under a flow ofnitrogen. NaOEt (25.2 g) was added and stirred for 10 minutes. Cutsodium metal was added to the mixture at −55° C. to about −70° C. infive portions. The reaction is monitored by HPLC analysis to follow thecourse of the Birch reduction. A total of 4.80 g sodium was necessaryfor completion of the reaction. After stirring another 30 min., themixture was allowed to warm to 0-10° C. The ammonia evaporated onwarming. The reaction was quenched with HCO₂H/H₂O and NH₄Cl/H₂O to pH 6to 8 and then diluted to a total volume of 2000 mL with water. Thesuspension was stirred for 30 minutes and filtered. The solid obtainedwas washed with water (150 mL×4) and was dried under a flow of airovernight to give the product as powder, 25.3 g.

Example 13 Preparation of Formula 22

The compound of Example 8 (24 g) was suspended in HCO₂Pr (850 mL) andheated to reflux for 3 hours. The solvent (550 mL) was removed bydistillation. The remaining suspension with stirring was allowed to coolto RT over a 30 minute period. The solids were separated by filtrationand then washed with ether (50 mL×4) followed by hexane (50 mL×2). Afterdrying under an air flow for 2 hours, the product remained as a powder,21.3 g. Another 3.63 g of product was recovered by removing thevolatiles under vacuum from the combined filtrates and washes.

Example 14 Preparation of Formula 23

The compound of Example 13 (1.0 g) was stirred in 88% HCO₂H/H₂O (12 mL)for 30 minutes to form a brown solution. The solution was dilutedfurther with water (50 mL) and extracted with ethyl acetate (25 mL×2).The combined organic layers were washed with water (25 mL×3) and thevolatile components removed under vacuum. The remaining solid wasredissolved in ethyl acetate followed y removal of the solvent underreduced pressure to afford 0.80 g of product as a solid.

Example 15 Preparation of Formula 24

The pre-cyclized intermediate of Example 14 (1.00 g) was dissolved inCHCl₃ (20 mL) and added over 15 minutes to trifluoromethanesulfonic acid(5 mL) cooled to about −40° C. to −20° C. This reaction mixture wasallowed to warm to RT and stir overnight. The mixture was diluted with200 mL H₂O and 200 mL ethyl acetate. NH₄OH (28%) was added to adjust pHto 8.5 and stirred for 2 hours. HCO₂H was added until pH was 4. Afterstirring for 0.5 hour, the phases were separated. The water layer wasextracted with ethyl acetate (100 mL). The combined organic layers werewashed with 0.01 N HCl (200 mL×3) dried over K₂SO₄ and filtered. Afterthe solvents were removed under reduced pressure, 1.05 g of solidremained. The product was isolated from the mixture by HPLC.

Example 16 Preparation of Formula 27

Formula 27 was prepared according to Example 13 with F as the halogen.

Example 17 Preparation of Formula 28

Formula 28 was prepared according to Example 12, with F as the halogen.

Example 18 Preparation of Formula 29

Formula 29 is prepared according to Example 14, substituting theN-formyl group with a free amino group for the compound of Example 13.

Example 19 Preparation of Formula 30

The compound of Example 13 (0.50 g) was dissolved in MeSO₃H (5 mL) andallowed to stand for 2.5 h before addition to a solution of NH₄OH inMeOH (100 mL). The pH was adjusted to 4. The mixture was diluted withwater (100 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with NaH₂PO₄ solution (2×100 mL), dried overNa₂SO₄ and filtered. The filtered solution was placed under vacuum toremove the volatile solvents. 0.52 Gram of solid crude product remained.HPLC analysis of the crude indicated that the solid contained 90%α,β-ketone, Formula 30.

Example 20 Preparation of Formula 31

Formula 31 is a byproduct of the acid-catalyzed rearrangement ofcompound formed in Example 19.

Example 21 Preparation of Formula 32

Formula 32 is a byproduct of the acid-catalyzed rearrangement of thecompound formed in Example 18.

Example 22 Preparation of Formula 33

Formula 33 is prepared according to Example 19, substituting thecompound of Formula 29 for the compound of Formula 23.

1. A method for the synthesis of an opiate intermediate, the methodcomprising: a) reacting a compound of Formula 1

wherein X is F or Cl; with at least one halide selected from the groupconsisting of sulfonyl halide and phosphorous halide to form a compoundof Formula 2;

wherein X is F or Cl; X₁ is Cl or Br; and Y is SO when a sulfonyl halideis used, and P when a phosphorous halide is used; b) reacting thecompound of Formula 2 with a compound of Formula 3

wherein R′ is an alkyl, aryl or acyl group; in the presence of at leastone base to form a compound of Formula 4;

wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group; c)reacting the compound of Formula 4 with at least one phosphoryl halideand then hydrolyzing to form a compound of Formula 5;

wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group; d)reacting the compound of Formula 5 as a free imine or imine salt with atleast one reducing agent to form a compound of Formula 6;

wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group; e)selectively reducing the compound of Formula 6 to form a compound ofFormula 7;

wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group; f)reacting the compound of Formula 7 with at least one formic acid esterto form a compound of Formula 8;

wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl; and R isselected from the group consisting of H, alkyl, aryl, acyl, formyl,COR″, COOR″, benzyl, alkyl and sulfonamide; and wherein R″ is selectedfrom the group consisting of alkyl or aryl; g) hydrolyzing the compoundof Formula 8 forms a compound of Formula 9; and

wherein X is a F or Cl; and R is selected from the group consisting ofan H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, and sulfonamide;and wherein R″ is selected from the group consisting of alkyl or aryl;h) converting the compound of Formula 9 under Grewe cyclizationconditions in at least one strong acid to form an opiate intermediatecompound of Formula 10,

wherein X is a F or Cl; and R is selected from the group consisting ofan H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, (methyl), andsulfonamide; wherein R″ is selected from the group consisting of alkylor aryl.
 2. A method for the synthesis of an opiate intermediate, themethod comprising converting Formula 9

wherein X is a F or Cl; and R is selected from the group consisting ofan H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, and sulfonamide;and wherein R″ is selected from the group consisting of alkyl or aryl;by Grewe cyclization to form an opiate intermediate compound of Formula10

wherein R is an H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, orsulfonamide; and wherein R″ is selected from the group consisting ofalkyl or aryl.
 3. The method of claim 2 wherein the Grewe cyclization isaccomplished in acid medium including an acid selected from the groupconsisting of hydrofluoric acid, methanesulfonic acid, p-toluenesulfonicacid, benzenesulfonic acid, 2-mesitylenesulfonic acid, sulfuric acid,trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid,Lewis acids and mixtures thereof.
 4. A method for the synthesis of anopiate intermediate, the method comprising: a) reacting a compound ofFormula 15

with at least one sulfinyl halide to form a compound of Formula 16;

b) reacting the compound of Formula 16 with a compound of Formula 17;

in the presence of at least one base to form a compound according toFormula 18;

c) reacting the compound of Formula 18 with at least one phosphorylhalide and then hydrolyzing to form a compound according to Formula 19;

d) reacting the compound of Formula 19 as a free imine with at least onereducing agent in at least one solvent to form a compound of Formula 20;

e) selectively reducing the compound of Formula 20 to form a compound ofFormula 21;

f) reacting Formula 21 with at least one formic acid ester to formFormula 22;

g) hydrolyzing Formula 22 to form a compound of Formula 23; and

h) converting Formula 23 under Grewe cyclization conditions in a strongacid to form an opiate intermediate compound of Formula 24


5. A method for the synthesis of an opiate intermediate, the methodcomprising converting Formula 23

under Grewe cyclization conditions in at least one acid to form anopiate intermediate compound of Formula
 24. 6. A compound according toFormula 24


7. The method of claim 1 wherein R is selected from the group consistingof methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,cyclopropylmethyl, cyclobutylmethyl, allyl and phenacyl sulfonamide. 8.The method of claim 1 wherein R is SO₂CH₂COPh.
 9. The method of claim 2wherein R is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl,cyclobutylmethyl, allyl and phenacyl sulfonamide.
 10. The method ofclaim 2 wherein R is SO₂CH₂COPh.